Isosorbide-5-mononitrate (I) is a compound which is currently much sought after in the pharmaceutical field because of its therapeutic properties in the treatment of coronary illnesses, in particular in the treatment of angina pectoris.
Isosorbide-2,5-dinitrate (ISDN) is known to exhibit an analogous pharmacological action. However, isosorbide-5-mononitrate has the following advantages (W. Schaumann, Medwelt Bd. 32/Heft 14a 1981; T. Taylor. L. F. Chasseaud, R. Major, E. Doyle and A. Darragh, Biopharm. & Drug Disp., Vol. 2, 255-263, 1981):
(a) In the metabolic process it provides only one mole of nitric acid instead of two. PA0 (b) In contrast to ISDN which metabolises into its two mononitrate isomers, it consists of a single active substance rather than three substances, the concentration ratios and thus the activities of which vary mutually with time. PA0 (c) It undergoes much slower metabolism and therefore exhibits a more lasting action. PA0 (d) It becomes distributed not only within the plasma but also throughout a much wider extent which can be approximated to that of the total body water.
One difficulty which makes the synthesis of isosorbide-5-mononitrate (I) costly is the need to prepare it by a selective method which enables it to be easily separated from its isosorbide-2,5-dinitrate isomer.
Various processes are known in the art for preparing isosorbide-5-mononitrate (I).
For example, a process is known for preparing isosorbide-5-mononitrate (I) by direct nitration of isosorbide (III) ##STR5## (I. G. Csizmadia, L. D. Hayward, Photochem. Photobiol. 4, 657, 1975; German Pat. No. 2,221,080).
According to a further process, isosorbide-5-mononitrate is prepared by partial basic or acid hydrolysis of isosorbide-2,5-dinitrate (L. D. Hayward et al., Can. J. Chem., 45, 2191, 1967).
These two processes involve dangerous operations because of which they are difficult to apply, and also give low yields.
According to further processes, isosorbide (III) is firstly protected in position 2, for example by acylation, and is then nitrated in position 5, after which the position 2 protector group is removed by hydrolysis (U.S.A. Pat. No. 4,065,488, German Pat. No. 2,951,934 and European Pat. No. 0045076).
According to a modification (European Pat. No. 0057847), the 2-acyl derivative which forms from the other components in the presence of catalysts is distilled from the reaction mixture. A process is also known (German Pat. No. 2,903,927) which leads to the preparation of (I) from isomannide by tosylation, transesterification, nitration and hydrolysis.
A process is also known based on the reduction of isosorbide-2,5-dinitrate, in which hydrazine hydrate is used as the reagent (French Pat. No. 2,103,906).
This however is a non-selective process in that both the monosubstituted isomers form in a ratio which is insufficiently high to allow economically convenient separation. Moreover, hydrazine is a known carcinogen.
All known processes are difficult to apply industrially.